The overall goal of this research program is to investigate a novel trafficking mechanism for the AMPA receptor that is the major mediator of fast excitatory synaptic transmission in the brain. The applicant for the K99/R00 award, Dr. Wei Lu, currently is a postdoctoral fellow working in Dr. Roger Nicoll's lab at UCSF. Dr. Lu's long- term research goal is to combine biochemical techniques with electrophysiology and genetics to study the molecular mechanisms for synaptic plasticity. Dr. Lu's long-term career goal is to establish himself as an independent scientist in a tenure-track academic position. AMPA receptor trafficking into and out of synapses is a major mechanism for synaptic plasticity that is a cellular model for learning and memory and is implicated in the pathogenesis of many mental illnesses. However, molecular underpinnings for AMPA receptor trafficking remain largely elusive. By using an innovative approach, the molecular replacement in an AMPA receptor null- background, Dr. Lu has made a novel discovery that a hitherto overlooked cytoplasmic loop domain plays an essential and specific role in targeting AMPA receptors to the synapse. As this mechanism for receptor trafficking is completely unexplored in the existing literature, he proposes to study the function of this intracellular loop domain in AMPA receptor traficking by adresing folowing thre specific aims: 1) to determine the role for this loop domain of the GluA1 subunit in synaptic transmission and animal behavior (mentored phase);2) to determine the role of a novel binding partner of the GluA1 loop domain in AMPA receptor trafficking (independent phase);3) to test the hypothesis that the GluA3 loop domain plays a role in AMPA receptor trafficking (independent phase). Dual whole-cell voltage-clamp recordings, outside-out patch recordings, biochemical and behavioral assays, and molecular biological tools will be employed to address the specific aims. Dr. Lu's career development plan includes receiving mentorship in neurophysiology in Dr. Nicoll's lab, receiving mentorship in biochemistry in Dr. Edwards's lab and professional trainings at UCSF during the mentored phase. The mentored phase will facilitate Dr. Lu's transition to independence by equipping him with new research and career skills and by publishing 2-3 high quality scientific papers. The public health relevance of Dr. Lu's research program includes providing mechanistic insights into learning and memory, and into the etiology of a variety of mental illnesses, including autism, depression, schizophrenia and mental retardation. As mental illness affects millions of people in the United States, Dr. Lu's research will generate novel knowledge at the molecular level for designing effective therapeutic reagents for these mental disorders. PUBLIC HEALTH RELEVANCE: AMPAR trafficking has been implicated in a variety of neurological diseases, and several compounds targeting AMPARs are currently in clinical for a variety of mental illnesses. The novel mechanism for regulating AMPAR trafficking by AMPAR Loop1 region represents a significant progress in basic neuroscience research for understanding the regulation of AMPAR trafficking, and thus will generate novel knowledge for designing effective therapeutic reagents targeting AMPARs for mental illness. ! !